Catalytic Asymmetric Mannich Reactions of Glycine Derivatives with Imines. A New Approach to Optically Active α,β-Diamino Acid Derivatives

• Published in: Journal of organic chemistry 2003-04, Vol.68 (7), p.2583-2591
• Main Authors: Bernardi, Luca, Gothelf, Aase S, Hazell, Rita G, Jørgensen, Karl Anker
• Format: Article
• Language: English
• Subjects: Aliphatic compounds; Amino Acids - chemical synthesis; Catalysis; Chemistry; Exact sciences and technology; Glycine - analogs & derivatives; Glycine - chemistry; Imines - chemistry; Indicators and Reagents; Models, Molecular; Molecular Conformation; Molecular Structure; Organic chemistry; Preparations and properties; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo026766u

Imines of glycine alkyl esters react with imines in a diastereo- and highly enantioselective Mannich reaction in the presence of chiral copper(I) complexes as the catalyst to give optically active α,β-diamino acid derivatives. A series of imines of glycine esters derived from glycine and aromatic carbonyl compounds has been screened as substrates for the Mannich reaction with different imines in the presence of various combinations of metal salts and chiral ligands. The benzophenone imine of glycine esters was found to react with N-protected imines in a diastereoselective fashion giving functionalized α,β-diamino acid esters with excellent enantioselectivities. The most effective chiral catalysts are chiral copper(I) complexes having phosphino-oxazoline (P,N)-ligands, and among these ligands, those derived from (1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene gave the best results. The scope of this new catalytic asymmetric reaction of the benzophenone imine glycine esters is demonstrated for the reaction with different N-protected-C-aryl and C-alkyl imines giving the Mannich adducts with excellent optical purity. Furthermore, the synthetic aspects of the reaction are presented by converting the Mannich adducts into α,β-diamino acid derivatives. The relative and absolute configuration of the Mannich adduct have been determined and based on the stereochemical outcome of the reaction a tetrahedral chiral-copper(I)-imino glycine alkyl ester intermediate is proposed. In this intermediate the Re-face of the benzophenone imine glycine ester is shielded by the chiral ligand leaving the Si-face available for approach of the Si-face of the imine. A series of semiempirical calculations has been performed to support the structure of the tetrahedral chiral-copper(I) complex and to account for the influence of the substituents in the chiral phosphino-oxazoline ligands.